Abstract 419: Cooperative interactions between p53 and NFκB enhance cell plasticity

Abstract

Abstract Breast cancer prevention, diagnosis and treatment have improved during recent years. However, despite these scientific and clinical improvements, breast cancer survival rate has not substantially increased, due to cancer recurrence and metastatic spread. It is therefore important to further investigate the mechanisms and causes responsible for breast cancer metastasis. The p53 and NFκB sequence-specific transcription factors (TFs) play crucial roles in cell proliferation and survival with critical, even if typically opposite, effects on cancer progression. To investigate a possible crosstalk between p53 and NFκB driven by chemotherapy-induced responses in the context of an inflammatory microenvironment, we performed a proof of concept study using MCF7 cells. Transcriptome analyses upon single or combined treatments with doxorubicin (Doxo) and the NFκB inducer Tumor Necrosis Factor-alpha (TNFα) were performed. Expression microarrays experiments identified a common set of synergistically up-regulated genes upon combined drug treatments in different cellular models of breast and lung carcinomas. This gene signature was enriched in inflammation, proliferation and metastasis gene functions, according to gene ontology and pathway analysis. Interestingly, the migratory phenotypes exhibited by our cell models significantly differed upon single and combined drug treatments and exhibited cell-type specificity. For a selected group of genes synergistically up-regulated upon Doxo+TNFα we were able to demonstrate by ChIP analysis a direct binding of p53 and NFκB and we uncovered LAMP3 and ETV7 as new p53-NFκB direct target genes. We also demonstrated that the combined Doxo+TNFα treatment was not only able to disrupt the 3D architecture of mammary acini observed with MCF10A primary cells grown within matrigel, but also to stimulate the tube-forming potential of Human Umbilical Vein Endothelial Cells (HUVEC). Furthermore, a signature of 29 Doxo+TNFα (DT-29) highly synergistic genes exhibited prognostic value for luminal breast cancer patients, with adverse outcome correlating with higher relative expression (based on Kaplan-Meier plotter tool). We further used available experimental data sets (RNA-seq measurements from Gene Expression Omnibus) both from breast cancer cell lines (luminal-like vs basal-like breast cancer cells) and breast cancer patients (ER positive vs Triple Negative Breast Cancer, TNBC and vs healthy adjacent tissues). The expression of DT-29 gene signature was analyzed and compared among the different groups of samples. The most statistically relevant genes differentially expressed among the different groups were involved in the STAT3-driven pathways and were prevalently highly expressed in TNBC patients and cell lines. We propose that the crosstalk between p53 and NFκB can lead to the activation of specific gene expression programs that may impact on cancer phenotypes and potentially modify the efficacy of cancer therapy. Citation Format: Federica Alessandrini, Vasundhara Sharma, Alessandra Bisio, Sara Zaccara, Alberto Inga, Yari Ciribilli. Cooperative interactions between p53 and NFκB enhance cell plasticity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 419. doi:10.1158/1538-7445.AM2015-419